Department of Pharmaceutical Science, University of Oklahoma Health Science Center, 1110 N. Stonewall, Oklahoma City, OK, 73117, United States.
College of Medicine Core Facilities, University of Oklahoma Health Science Center, 975 NE 10th Street, Oklahoma City, OK, 73104, United States.
Toxicology. 2018 Dec 1;410:1-9. doi: 10.1016/j.tox.2018.08.014. Epub 2018 Aug 29.
Irritant contact dermatitis (ICD) is a cutaneous inflammatory response to a variety of triggers that requires no sensitization and accounts for up to 80% of occupational dermatitis cases. IL-6 has been alternately associated with both allergic and irritant dermatitis and is closely linked to skin wound healing, therefore making it an ideal candidate to investigate in the mechanism of ICD.
Despite being a well-known pro-inflammatory cytokine, IL-6 deficient (IL-6KO) mice show much more severe ICD than controls. Transcriptome analysis was employed to examine irritant-exposed and control skin samples from C57BL/6 and IL-6KO mice. Over 1900 transcripts were found differentially modulated between C57 (1184 total) and IL-6KO (802 total) mice with the magnitude of expression significantly disparate. Overall gene ontology revealed metabolic and cellular enriched functional processes but numerous pro-inflammatory and immune associated genes (Cxcl2, Cxcl3, Cxcl5, Acod, Hamp, c-Lectins, for example), keratin associated genes (Krt6b and various Krtaps), and members of the Sprr and Lce family, which promote skin barrier integrity and keratinocyte functions, were also differentially modulated.
The altered expression of these genes may provide a potential mechanism to explain the increased ICD severity in IL-6-deficient mice. Overall, this study offers new insight into the pathogenesis of ICD, indicates new mediators/biomarkers that may influence the variability of responses to irritants and provides potential targets for therapeutic development.
刺激性接触性皮炎（ICD）是一种对多种刺激物的皮肤炎症反应，不需要致敏，占职业性皮炎病例的 80%。白细胞介素 6（IL-6）与变应性和刺激性皮炎交替相关，与皮肤伤口愈合密切相关，因此是研究 ICD 发病机制的理想候选物。
尽管白细胞介素 6 缺乏（IL-6KO）小鼠是一种众所周知的促炎细胞因子，但它们表现出比对照组更严重的 ICD。采用转录组分析方法，检测 C57BL/6 和 IL-6KO 小鼠的刺激性暴露和对照皮肤样本。在 C57（1184 个总）和 IL-6KO（802 个总）小鼠之间发现了 1900 多个转录本差异表达，表达量差异显著。总体基因本体论揭示了代谢和细胞丰富的功能过程，但也有许多促炎和免疫相关基因（如 Cxcl2、Cxcl3、Cxcl5、Acod、Hamp、c-凝集素等）、角蛋白相关基因（Krt6b 和各种 Krtaps）以及 Sprr 和 Lce 家族的成员也被差异调节，这些成员促进皮肤屏障完整性和角质形成细胞功能。
这些基因的表达改变可能为解释 IL-6 缺乏小鼠 ICD 严重程度增加提供潜在机制。总的来说，这项研究为 ICD 的发病机制提供了新的见解，表明了可能影响对刺激物反应变异性的新介质/生物标志物，并为治疗性开发提供了潜在的靶点。
